We will investigate the regulation and expression of the DNA repair enzyme, beta-polymerase, in clinical conditions complicated by a high incidence of malignancy and in human tumors which have become resistant to chemotherapeutic agents. Our objectives are: (1) to determine if the development of non-Hodgkin's lymphoma (NHL) in human immunodeficiency virus (HIV)-infected patients receiving azidothymidine (AZT) or in transplant recipients on cyclosporine therapy is associated with a down-regulation in the expression of beta-polymerase, (2) to examine the childhood chromosomal instability syndromes such as Fanconi anemia for a disregulation of beta- polymerase, (3) to investigate the function of beta-polymerase in human cancer cells which have acquired a resistance to alkylating agents, and (4) to study the effects of an array of drugs, transforming oncogene products, and HIV transcriptional regulatory proteins (tat and rev) on the regulation of the human beta-polymerase gene. Conventional Northern blotting and in situ hybridization techniques will be employed to assess beta-polymerase transcription in all these patients and their tumors. Normal peripheral blood lymphocytes, as well as B and T-cell lines, will be cultured in the presence of AZT, cyclosporine, and other agents to define their ability to suppress the constitutive expression of beta-polymerase. Human cell lines will also be transfected with tat, rev or oncogene expressing plasmids to determine if these nuclear proteins act as positive or negative transcriptional regulatory elements on the expression of beta-polymerase. In a similar manner, we will test the effect of these transcriptional factors on the human beta-polymerase promoter in transient co-transfection assays. Finally, we will utilize cancer cell lines which have been made resistant to alkylating agents as a model for studying the contributions of beta-polymerase and oncogene expression to this resistant phenotype. Collectively these studies will enhance our understanding of the pathogenesis of HIV and cyclosporine-related NHL, as well as provide insight into other pre-malignant conditions associated with defects in DNA repair. Moreover, our efforts may lead to a rational strategy for regulating the expression of beta-polymerase in lymphocytes to potentially circumvent the risk of malignant transformation or the emergence of chemotherapy resistance.